DE1905683A1 - Therapeutically effective substituted 2-amino-4-hydroxymethyl-6-aminotriazine-1,3,5- and processes for their preparation - Google Patents

Description

D-8023 Mun-Jen - Pullach WlK, cfjl ;. 2. Γ. Μώ, ι. 7950570.7931732

Dr ₆ S.-J »/ Str. Munich-Pullach, February 3, 1969

Jan Marcel Didier ARON-SAMUEL, 116, rue Carnot 92 SlIRESNES France and Jean Jacques STERNE, 17, Boulevard Karl Marx 95 ARGENTEUIL, France

Therapeutically effective substituted 2-amino-4-hydroxymethyl-6-aminotriazine-1,3,5 and methods of making them

The invention relates to therapeutically effective 2-amino-4-hydroxymethyl-6-aiaino-triazine-1 _s 3 ₈ 5 of the general formula

R-CH-C N

OH ^ N C

OH ^ N = C R

where mean: ₍

R - hydrogen, a alkyl, methylenedioaqf-phenyl or an optionally by halogen, alkyl, haloalkyl or alkoxy radicals mono-, di- or trisubstituted Phenyl group

R ¹ and R "- either hydrogen, an alkyl, alkenyl, cycloalkyl, dialkylamino-alkyl, peridinoalkyl or

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Morpholinoalkyl group, with only one of the substituents

R ¹ and R "is hydrogen or alkyl, or

NR ¹ R "- an optionally C-alkyl-substituted heterocyclij see group with a second hetero nitrogen atom, the

is substituted by an alkyl, alkenyl, hydroxyalkyl or an optionally substituted phenyl radical,

j and salts of the triazines (I)

The alkyl, alkenyl, hydroxyalkyl and alkoxy radicals mentioned are "preferably lower radicals, those represented by the R ¹ and R" and the heterocyclic group UR ¹ R "are one from 5 _t 6 *: ad Group consisting of 7 ring atoms.

The triazines (I) can be present in a tautomeric form by the Nuclear substituents of the triazine nucleus from the amino to the imino form skip carbon atom connected to the radical R is asymmetrical, so that the triazines (I) are thus in an optically active or * racemic form can pass

The triazines (I), which mainly act on the central nervous system, are anxiolytic (anxiety) and mood-lifting (Antidepressants), stimulating (stimulants), hallucinations (anti-hallucinants) and tremors) _ as well as Heart and at-

009810/1807

stimulating agents (oardiorespiration stimulants), which are usually used as therapeutic agents when bound to a suitable carrier Triazines (I) also effective as herbicides «

The process according to the invention for the preparation of the triazines (. Is characterized in that a (^ -hydroxycarboxylic acid the formula

E-CH (OH) - 00 - OH II

with a biguanide of the formula

- O (NH) - NH - G (NH) - NE ¹ R ", III

wherein E, R ¹ and R "or NR ¹ R" have the above meaning, converts and separates the triazine (I) from the reaction mixture in the usual way.

The Cf- hydroxycarboxylic acids (II) can be used both as free acids and in bound form, which is reactive, - for example as anhydrides, acyl halides, esters, amides and hydrazides of the acids (II).

The reaction can be carried out in the absence of solvent and catalyst by means of etching at at least 100 ⁰ G, but it is carried out in the presence of alkaline. Favors catalysts,

009810/18 07

- preferably by an alkali metal alcoholate, such as sodium methylate,

If the reaction is catalyzed, it is useful to do this Biguanide (III) in fora of a salt, especially a hydrohalide, preferably a hydrochloride, dihydrochloride, hydrobromide or dihydrobromide, to be used in situ, by releasing the mguamide from the salt with as much of an alkaline agent as an equivalent of the alkaline agent remains, which serves as a catalyst in the subsequent reaction stoichiometric amount of C £ -hydroxycarboxylic acid (II) or »de Descendant and converts to triazine (I)

The reaction according to the invention is usually carried out in the alcoholic Medium carried out at normal temperature for 2 to 48 hours or under reflux in half an hour, whereupon the reaction mixture is treated with water · Immediately or after a few hours. The triazine (I) precipitates; it is dried and recrystallized after separation.

It can be advantageous to use the triazine (I) from the reaction mixture to be extracted using a suitable solvent such as methylene chloride, followed by evaporation of the solvent and the residue is crystallized from an appropriate solvent, among other things

00 9810/1807

for recrystallizing the pipes. Triazines (I) are used z · £ · acetonitrile, alcohols, ketones, water or dimethylformamide.

Some of the biguanides (III) are new compounds, viz those who have the formula

lIl

O IV

NH NH ^X R ""

correspond, in which R ¹ "and S ⁸ " ⁸ - either .hydrogen, an alkyl, dialkylaainoalkyl, F "^ © ridinoalkyl or morpholinoalkyl group, with only one of the Sufestituenten E ⁸ and R" hydrogen or alkyl is ₉ or one? ER ¹ · ⁸ R ¹ · '' - an optionally C-substituted heteroeyeliecMe group alt a second hetero nitrogen atom which is substituted by an alkyl, alkenyl, hydroxyalkyl or an optionally substituted phenyl radical, where d®; e alkyl radical is not a methyl radical if the heterocyclic group is a ® BLperazino group.

These biguanides (IV) are effective as such against diabetes, inflammation and anticholinergic and are therefore also valuable therapeutic agents. They are obtained by adding a salt of an amine of the formula HNB ¹ ' ¹ R ¹ ' or a corresponding heterocycle , wherein R ¹ "and R ¹ ' ¹ ^ or ^ NR" ^ ¹ · "have the above meaning, with a cyanguanidine of the formula

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₂ in melt flow or in a solvent

such as butanol or ethylene glycol ether. (See the stage (A) of Examples 1 and 2). In Table I is a number new biguanide (III) listed.

example 1

2-Amino-4- C £ -hydro3cybenzyl-6- (diethylaminoethylamino) -triazine-1,3,5.

(A): Nan heated a mixture of in a flask

84 grams of cyanguanidine

250 g ethylene glycol monoethyl ether ("Oellosolve *) 189 g of 2- (diethylamino) ethylamine dihydrochloride under reflux for 3 hours. After cooling, it is poured into 900 ml To acetone, the gummy product obtained dissolves in 150 ml Methanoljund pours in 500 ml of acetone until constant cloudiness is obtained. The slowly crystallizing product is made from abs. Recrystallized ethanol

Yield: 114 g of 1-Γ (2 ■ -diethylamino) -äthylj-biguanide dihydrochloride. F.I7I-I73 ⁰ 0 (from Thiele tubes). Analysis: found % 01 25.97i N 30.90; calculated% 01.25.96; N 30.77

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Example 2

2-Amino-4 - ^ - ^1- hydroxy- (3 ', 4 ¹ -methylenedioxy) -benzyl ^ -6- (4 ^l -n propylpiperazinyl) -triaain-1,3 * 5 ·

(A) Put a mixture of 21g cyanguanidine in a flask

400 ml of butanol under reflux in portions within egg 72.5 gN-n-propylpiperazine-lihydrobromide added within an hour After refluxing for 5 hours, the biguanide falls when cooling off; it is recrystallized from ethanol at 95 ° C «

Yield 72 g of i-biguanyl-4-n-propylpiperazine dibydrobromide · F «232-234 ° C (in an ihiele tube) · Analysis: found. % Br 42.74} N 22.53; calc.% Br 42.72; N22.46

(B) Stir in a flask for several minutes:

187 g (0.05 mol) i-biguanyl-4-n-propyl-

piperazine dihydrobromide,

300 ml of methanol and

750 ml of methanolic 2N sodium methylate

and a solution of 112 g of 3 »4-methylenedioxymandelic acid ethyl ester for the mixture poured in 100 ml of methanol

The mixture is stirred for 4 hours, left to stand for 24 hours and then 100 ml of the st.

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Water to «The precipitated rubber-like product hardens in 3 hours It is washed with water, dried and recrystallized from acetonitrile «

Yield: 65 g of the base · 148-150 ⁰ C (In Thiele Röhrehen) · Analysis: Found. % C 58.10; H 6.72; 0 12.91; N 22.72 ', calc. % C 58.05; H 6.50; 0 12.89; N 22.57. The BMN spectrum corresponds to the structure

Example 3

2-Amino-4-hydroxyheptyl-6- (4 * -methylpiperazinyl) -triazine-1,3,5.

To a mixture of seduced in a flask for several minutes 51.5 g (0.2 mol) i-biguanyl-4-ethyl-piperazine-dihydrochlo

rid,

140 al methanol and
300 ml methanolic 2 N sodium methylate solution,

pouring a solution of 37.6 g (0.2 mol) of C £ -hydroxycapryl-

acid ethyl ester in 20 ml of methanol to

After stirring for 5 hours and standing for 46 hours, 400 ml of distilled water are poured in. The resulting solution is extracted with methylene chloride, the extracts are washed with water, dried and the solvent is evaporated. The yellow oil that remains

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is taken up in 100 ml of absolute ethanol, contains hydrogen chloride total isopropanol added up to pH2, with abs. Ethanol diluted, filtered and recrystallized from 500 ml abs «ethanol

Yield 15 g of the Dihydrochloride, ϊ ¹ · 270 ⁰ C (dec, in Tiele tube Analysis:.. Found% C 47.47; H 8.08; N 21.89 0 3,79i} about 47% 0. 24; H 7.87; 0 4.20; N 22.05. The RMN spectrum corresponds to the structure. F of the crystallized base 80-82 ° G,

(B). Stir in a flask for a few minutes

136 g (0.5 mol) i - ^ '- diethylamino ^ äthyll-biguaiiid, 300 ml of methanol and

750 ml of methanolic 2N sodium methylate

and pour a solution of 90g of ethyl mandelate into the mixture in 100 ml of methanol, then stirred for 4 h, left to stand for 24 h and stirred again for 4 h.

This is followed by pouring in 100 ml of the st. Water a full Resolution achieved * The solution is extracted 3 times with 500 ml of methylene chloride, the extracts are washed with water, dried and the solvent is evaporated off. The UI obtained is in Dissolved acetonitrile, refluxed and sidt Aktivkohl® cleaned.

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The triazine crystallizes out on cooling and is recrystallized from isopropanol · F. 134 ^° C. (in a Thiele tube). Analysis: found % G 60.71; H 8.01; 0 5 »16; N 26.65} calc.% 0 60.75t H 7.65; 0 5.06; N 26.56. The BMN spectrum corresponds to the structure

Example 4

2-Asi.no-4 - (^ - hydroxy-4 ¹ -me thoxy-ben ^ yl) -6- (allylamine ») -

triazine-1,3f5 · According to Example 3 is obtained from

9 g allyl bigvmid hydrochloride, 10> 5g p-Methoxyandelic acid, ethyl ester, 50 ml of methanolic 2 N sodium methylate. and 40 ml of methanol

3.3 g of the 0iriazine _# f.162 ^o O (in the Ihiele-Höhrchen), analysis: found % C 58.58; H 6.13i 0 11.28; N 24.30; calc. # G 58.52; H 5.96; 0 11.14; N 24.38 The HMN spectrum corresponds to the structure

Example 5

2-Amino-4 - (<& -hydroxy-3 '-methoxybenzyl) -6- (4' -methylpipera- ? inyl) -triazine-1,315

Aub 12 ,, g Ί> ^ xguar. 7l-4 -gi ethylpiperazine dihydrochloride »

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10.5 S m-methoxymandelic acid ethyl ester, 75 ml of methanolic 2N sodium methylate and 40 ml of methanol

3 g of the triazine obtained 3? .14-5 ° G (in a Thiele tube) analysis: found according to Example 3. % G 58.01} H 6.82; 0 9.85; N 25.46; % Q 58.16} H 6.71 i 0 9.69} N 25.44. THAT RMN- "Spectrum corresponds to the structure"

The triazines (I) obtained according to the preceding examples are recemic. Starting from optically active derivatives of the QC- hydrocarboxylic acids (II), for example from esters of the formula

- 0 * OH

enantiomorphic forms (optical antipodes) of the triazines (I) can be obtained, in particular those in which R is methyl or phenyl and HR ¹ R ¹ 'is a 4-methylpiperazinyl radical; these two triazines have melting points of 150 and 163 ° C and a rotational force (turning ability) Γ <£ of -12.5 or -18.7 ° in ethanol solution

Tables II to IV show a number of the Examples or a similar procedure prepared triazines (I) compiled and the latter for the sake of brevity

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with LA numbers, which are in the further tables and the description come back, denotes} as far as the triazines were prepared in the form of their hydrohalide salts or hydrates, is the Number of attached hydrohalide and water molecules given.

Results of toxic and pharmacological tests

These show the harmlessness and effectiveness of triazines (I) on the central nervous system by helping to remedy Ensure disturbances in the emotional life and behavior as well as the autonomic nervous system

The examination of the toxic doses in animals shows the enormous therapeutic scope of the triazines (I), since one almost always has to reach oral doses of 500 mg / kg in order to see the lower limit of DL, - _O appear V based «

Investigations of the chronic toxicity on batteries, which ia Oral doses of 10, 50 and 250 daily for 3 months mg / kg was administered - especially with the triazines LA 1674, 1676, 1689, 1692, 1693, 1703, 1705, 1? 78, 1793 unc 1798 - the absence of toxic signs both from the point of view of clinical and biological observations of the treated Animals as well as macro and microscopic examination

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of all organs and viscera.

The pharmacological investigation showed that the triazines (I) atets have an effect on the central nervous system in animals that have been made sick by a drug, whereas they are less effective in normal animals Essential findings in this regard are reproduced and given in tables for each examination. Insofar as injections were carried out in the experiments, they were intraperitoneal (i _e p «) and intravenous (iv) administrations, Ss shows:

Table VI: Inputs from apomorphine ₉ das ^ sX dogs vomiting ₉ when dogs had physical restlessness © (agitatio) veriarsash = te, certain triazines (I) counteracted (antagonism), while other friazines (I) increased the restlessness in rats ( Pot © B, sie: raag) _e

Table VII: When entering amphetamine (1-phenyl <~ 2-amim> pro ° - pan), which caused restlessness and chewing in rats, was caused by triazines (I) in one or both of the a counteraction appears

Table VIII: The toxicity of amphetamine inputs to mice tended to decrease due to triazine (I) intake

Table IZ: When entering the sleeping pill Pentobarbital® i.e. the 5-ethyl-5- (1-methylbutyl) -ba3? 'biti22 ^> gäiiz? 9 ₆ the mice in i. ρ, -doses of JO mg / kg in ^ i ^ ic ^ t, the sheep would be treated by numerous triazanes (I)

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strengthens

(Table X: When entering reserpine (3,4,5-trimethoxybenzoic acid methylreserpatester) in i.p. doses of 2 mg / kg, the hypothermia produced in mice was eliminated the! triazines (I) either strengthened or counteracted it; some triazines (I) had an antagonistic effect elfcnxalls against ptosis, and catalepsy reserpine diarrhea.

! Table XI: When tremorin was administered to Hausen in i.p doses of 20 μg / kg, the counteraction (antagonism) began depending on the triazine (I) used, with different

new cans | the effective oral mini dose in the test series was 1 mg / kg

! Table XII: The mi.ti; ice of a hot plate on paws of Jokes in mice would be caused by oral doses between 1 and 50 ag / kg of numerous triazines (I) decreased; other triazines shortened the response time of the home when exposed to the hot Plate.

Table XIII: After rapid administration of nicotine in IV doses of 1 mg / kg were often protected against by i.p. doses of a triazine (I) Seizures and mortality, - sometimes im Greg part, however, a potentiation.

Table XIV: Ge ^ s the soporific effect of chloral, the mice in i _e p.-doses of 300 mg / kg was inputted, worked triazines (I) by varying the input

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sleep time and duration of sleep

Table XV: Acted on the isolated rat duodenum Triazines (I) of the contraction caused by acetylcholine and / or barium chloride (contract! on) and in this way showed an atro pin and ρapaverine-like effect in the one from the Table of apparent dimensions

Further investigations showed the following:

1) · By i, v · injection of pentamethylenetetrazole in mice Cramps caused by certain triazines (I), in particular by LA 1697 ia a ί ρ dose of 10 mg / kg, reduced

2) · The pharmacological action of triazines (I) on healthy In the absence of any medical treatment, animals show no behavioral disturbance.

3) · Up to 100 mg / kg strong oral doses of triazine show in the Herenity von Hausen no change in performance in the pull test (test de la traction) and rotary pin test (test de la tige tournante).

4 ·) · For cats that are by means of de? Sodium salt of pentobarbital ("Nembutal'O were anesthetized, caused certain triazines (I) a tiny contraction of the blinking membrane (membrane nictitante), - e.g. by an IV dose of 5 mg / kg LA 16? 4-

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a contraction in strength as produced by IV administration of 2g / kg adrenaline, 5). Certain triazines (LA 1674, 1689, 1692, 1693, 1695 »1698, 1? 05, 1706, 1760, 1763» 1784, 1793) sinus bradycardia; z. B, an iv dose of 5 mg / kg LA 1793 reduced the dog's heart rate by an average of 15 % » 6) The electrocardiogram shows digital-like changes with iv doses of 5 mg / kg triazine (I) and above, namely a cupula-shaped senloing of the end phase and with higher doses a lengthening of the auriculo-ventricular and intraventricular conduction, - in particular through LA 1692 and 1693 7). I) - by oral doses of 50 mg / kg not at all or only in the amount of + 2 oi

8th). In rabbits in which respiratory depression was induced by 25 mg / kg morphine, a considerable improvement in lung ventilation can be achieved with certain triazines (LA 1674, 1692, 1693, 1784, 1793). 9) r In rabbits, in the awake, relaxed state, the cortical electroencephalogram shows with very small IV doses, such as those of 1 or 5 mg / kg triazine (especially LA 1674, 1689, 1693 »1703, 1705» 1707), Disorders and oral intake

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- 17 -

there would be repeatable changes lasting up to 2 hours, 10), The examination of inflammation - both in its first stage with orrageain (hot water extract from Carrageenan such as Icelandic moss), as well as in its second stage with filter paper discs - is made by triazines (I). especially through LA. I703, not affected.

From the above it can be seen that the triazines (I) are of great therapeutic interest, since they are essentially have psychotropic properties that are at least durcl have any of the following effects:

they have an effect on the existing effectiveness and effectiveness measurement (Aktivmetry), reinforcing this at low doses and slowing down at high doses;

they appear on the electroencephalogram as bulges (bouffees), - either as tips or as long waves;

they reduce or increase the toxicity of the Wake-up amines from the amphetamine group;

they are partly antagonists with regard to the central and peripheral effects of the ester alkaloid reserpine, on the other hand they behave in the opposite way equivalent;

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19056d3

they are very potent antitremorinants in low oral doses;

they have an oral breastfeeding effect (analgetisoh);

they are inhibitors of the sympathetic / * receptors;

they have an influence on the apomorphine effect and on catatonia induced by phenothiazines (2,3,5,6-dibenzo-1,4-thiazine) .;

they act on the cardiorespiratory system as analeptics and brachycardic, are therefore of great advantage over the currently used neuroleptics and antidepressants.

Their clinical uses have been shown to be consistent with what can be foreseen from the pharmacological examination In general, the effects are different and often opposite with weak and strong doses. Likewise, the indications do not agree: the adir small doses act more on neuroses, the strong doses on the other hand on psychoses; This explains the very broad Veräriohungsfächer (eventail de posologies). This changes between about 2 and 1000 mg for daily doses and about 1 to 500 mg for single doses, as is the case with regard to the effects genes on the central nervous system can be seen, for example, from the following - r ^ u:

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(a) LA 1689 acts - depending on the desired effect - in daily doses from 2 to 1000 mg as an anoxiolytic and antidepressant

(b) LA 1692 and 1693 show daily doses between 5 and 850 mg stimulating, anti-hallucinative and antidepressant properties

(c) LA. 1763 and I78I cure in daily doses of 25 to 750 mg endogenous depression.

(d) LA 1778, 1693 and 1798 act in doses between 15 and 500 mg against motor tremors

(e) LA 1703, 1755 and I8O3 are found in doses between 2 and 900 mg / kg, depending on the strength of the dose, effective across the range of anxiety neuroses, manic-depressive psychoses and hallucinogens

(f) LA 1692, 1693 and 1784 lead in daily doses from 100 to 1000 mg a measurable respiratory stimulation as well as a slowing down the heart activity and are therefore in breathing difficulties and therapeutically useful as a cardiovascular aaaleptic «

With general anesthesia intensify! Triazines (1) the Atauig facilitate awakening and reduce the diseases of the anesthesia · With heart failure, they slow down the heart and improve the heart balance (Sompenaefcion) »In clinically applicable doses, they lack hematological, real or hepatic toxicity . LA 1762 was found to be a modulator of the surrenal gland,

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! 905683

Triazines, for example, are therapeutically preferable LA 1674, 1689, 1692, 1693, 1697, 1703, 1750, 1755, 1762, 1793, 1798, 1803, 1814, 1815, 1816 and 1822.

The triazines (I) can be administered in the pharmaceutically suitable form, e.g. B. as capsules, tablets, coated tablets, Pellets and syrup or in suppository form mixed with appropriate carriers and additives. Entering can not only orally and rectally, but also parenterally through inte peritoneal, intravenous, or intramuscular injection, either dissolved or dispersed in a suitable solvent or bound to a retarding carrier.

It follows from the above that the traizins (I) thanks to the lack of toxicity and the presence of very extensive effects on the central nervous system important new therapeutic applications in neuropsychiatry as well as for respiratory and Enable cardiac resuscitation

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-li te III (i: r. Shiyle tube
c her.) Table I. al 3 Bnse or ^ -xlz 171-17 * Bi -upuic A HGl Decomp. 2Hf • ν 3 HOl ι 90 ii ä t hylani nc äthj'l U H ₂ OO _x .1 H ₃ U 2 * 6-2 * 7 Hi-3th: -lp :: inopropyl d 2 HGl Z'jrs. 132-134 . ii η fchyl s ^r ur. ο; ir ■ * v'l H H ₃ OO _x , 1 HpO 114-116 di.r.e thylaninoisopro- H HpOO " 1 '^ - 1CS iiibut-l-i-iro. ^ oryl H H ^ OO ₅ . H p Decomp. 103-105 dibutylaninoutyl H H ₂ OO ₃ -H ₂ O 186-1H8 ii; jrop-lnrr.in'j; rcp-l II 2 HGl 109-110 perhydr ^ zopinooro- • I Bure ; i r> e ri ii no ä b hyl H 2 HGl * f S I - - "· τ orpholinopropyl H 2 HOl 194-135 line t hrlar.ino äthy 1 Thyl 2 HGl 218-220 'line bhylaninoethyl Hth; 'l 2 HGl 93-100 Ii ^: i bh.yl '^ inoäthyl methyl base dineth; -laninopropyl 232-234 di ä thylinino ethyl isopro
pyi 2 HBr 218-220 ITR ¹ R ¹ ' 2 HBr 235-237 4-DrOpJrI -piper azii ^ l 2 HBr 168-170 4-i3opropyl- " 2 HBr Dec. 230-232 4-allyl- " 2 HGl Dec. 251-263 4- (hydrox: methyl) - " 3 HGl 215-217 4-phenyl- " 2 HBr 4- (4'-chlorophenyl) - ' ¹ 4-methyl-1,4- "erh3 / dr
pinyl

009S1D / 1807

BATH ORIGINAL

905683

T -JLV
abelle II = H piperidi
no ethyl • 168-169
LA 1783 Tri aaine 1 with R ' dineth :, ^r l-
aemii-ooropyl R \ ^ ' ν 11.-1 diet hylaraino
ethyl 171-173
LA 1766 H 146-148
LA 1787 102-104
LA 1820 methyl 99-100
LA 1785 38-90
LA 1619 IOI-IO3
LA 1749 ethyl 86-87
LA 165; 83-85
LA 1803 n-butyl 167-161;
CHOI)
LA 165V 130-131
LA 1756 38-99
LA 1807 n-hexyl 10 * 4-1 OC
LA 163 ' 75
LA 1789 122
LA 1831 phenyl LA 167 / 134-135
LA 1793 130-131
LA 1812 o-fluorophenyl 143-144
LA 1772 135-136
LA 1802 p-chlorophenyl 140
LA 1752 p-bromophenyl 138
LA 1770 138-139
LA 1841 o-chlorophenyl 130
LA 1780

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BATH ORIGINAL

Table Ha diethylamine
noethyl dimethyl
aminopropyl dimethylamino
propyl-2 141-142
LA 1813 ^^ * ^^^ R "
R ^ \ ^ Triazines I with R ¹ = H 136-138
LA 1801 Dhenyl β HyI 128
LA 1784 136
LA 1744 I7O-I72
LA 1794 n-fluorophenyl 104-106
LA 1776 ρ thiethyIphenyl 106
LA 1848 132-134
LA 1786 177-179
LA 1790 pi Rorjinyl-
phenyl 96-97
LA 1781 142
LA 1849 139-140
LA 1771 p-me thoxypheny; 128-129
LA 1782 τι - methoxy-
phenyl , 160
LA 1676 146-147
LA 1799 m- (trifluorme-
thyl) -phenyl 94-96
LA 163 ^ 129-130
LA 1747 129-131
LA 1751 3,4-dichloro
phenyl 139
LA 1795 166-168
LA 1830 183
LA 1775 m-chlorophenyl 68-70
LA 1798 I72-I73
LA I7O8 3,4,5-trimetho-
xyphenyl 3,4- (methylene
dioxy) phenyl 136
LA 1718

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E s ^^ H " cyclo
hexyl Table lib dipropylamino
propyl H morpholi-
nopropyl piperidi-
noethyl phenyl ! Triazines I with R ¹ = 108-110
LA 1836 dibutylamino
propyl p-methylphenyl 161-163
LA 1665 diethyla
mino-
propyl 98-99
LA 1821 LA 1743 166-168
LA 1832 O
O m-me tnoxyphenyl 104-106
LA 1763 13?
LA 1833 9810 3,4,5-trine tnoxypnenyl 120-122,
LA 1804 138-140
LA 17 «? / 180 3,4- (methylenedioxy) -
phenyl 103-104
LA 1791 II5-II7
LA 1788 150-151
LA 1748 -j 104-105
• LA 1758

CJJ OO

-X5-

Table III

ethyl

phenyl

Triazines I with substituted R ¹ and R ¹¹

H ¹

ι ι

methyl ^ dimäth? '! ·

124-126 LA 1815 dimethylaminorropyl

99-100
LA 1818

diethylaninoutyl

7th
LA 1314

91-93
LA 1617

diaethyla-EinoUfchyl

73-75
LA 1816

Table IV

f

iDriazine I with heterocyclic! Remainder rlR'R ¹ '

4-isopropyl-4-phenylpiperazi—
ayl.

phenyl) piperaainyl

1.4-per-

hydrodia-

zepinyl

ethyl

phenyl

109-110 LA 1806

149-151 LA 1759 153-155
LA 1842

190-193
LA 1633

123-125 LA 1824

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190 xl
ma bh? ^r l g25t "l-r ^ il Hthyl) - "jpera- I. ■ ^ ipera-
iiinyl -Xt- ! Table IVe
l'ria-sine I with heterocyclic! Heat IiH ¹ R ¹ ethyl 1 ¹ Sf-I '-7
_P LA 1687
150
LA 16PS LA 'i7 / 7
117-119 n- _W? .from LA "1703 11 "-117
Lt 17? - 116-117
LA 1305 10 ^ -104
Lit I75O η-butyl 110-120
LA 1702 i-butyl . ^ SOZerss.
(+ - HOl /
LA I7O6 ii-hexyl LA "17% n-uonyl L / i 1639
270 Zera.
(+, 'HOl ^ Li 17/9 86-87
l / A 1t34 n-tetradecyl 270 dec.
; +2 HOl)
LA 1707 phenyl LA18? ^ - p-fluorophenyl 163
LA 169? 158
LA 1773 192
LA 1823 155-156
LA 1753 p-chlorophenyl 12S
LA 1697 120
LA 1762. 116-118
LA 1800 ρ -br oaipheny 1 141-143
LA 1692 148
LA 1792 116
La 1822 136-138
LA 1696

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: -fluor? rhen. "l

: r: -chlc r: hen ^:! "

192-19 = 5

LA

LA 1G '/' i

210-21-

LA

of table I / a

133-134

LA 1774 4- (2'-hydroxy ä1; hyl) -piperazinyl

L / i 1754

009810/1807

. BATHROOM OHI0INAI,

-Xt- p-isoprorjyl-
pher.yl ι-allyl- '! -n.eth ₇ l- ■■ f-oropvl-H .Ä'rt " l ^A abile ITb p-mei / hoxyperiyl r, l n / l r.yl 4- (2'- in-rae thoxyphenyl 14th
LA 1'Qi ethyl)- ir .- (trif luorme bhyi
-phenyl 21-122
LA 1846 LA 1G90 • Jriaaiiie I with -10 u-ji'ccyclirohoin host; 2,4-dichlorophen_l LA 1705 113-119
LA 17 ⁽ '1 La'1757 3,4-dichloropheny 103-105
LA 1796 170-172
LA I704 123-139
LA 1754 3 , 4i-dimetho__y-
phenyl 142-143
LA 1709 3,4,5- trimethoxy
phenyl 163-165
LA 1699 3,4- (methylene
dioxy) -phenyl '. 108-110
LA 1691 oyolohe: qyl 172-
LA 1694 m-fluorophenyl 23-125
A 1808 156-168
LA 1698 148-150
LA 1778 159
LA 1760 156
LA 1845 65-167
A 1769

009810/1807

BAD OBiGlNAL

1905R83 product
LA -19 ' > 20ü ?. orally • off on > 100 Table V > 1000 i.p. i.V. > 100 1631 DI ^., - cans in n \ «: / lcg > 1000 1632 Lifted } 1000 1657 oral i.p " 1125 1574 > 1000 1676 > 5üO 1677 > 1000 1688 400 > 500 575 1689 > 1Ü00 > 1000 1690 1600 - > 100 > 2000 > 100 1691 2000 220 s ,, c. 600 200 1 ^ff > 92 1600 ^ 1500 1693 > 200 > 100 > 2000 > 1600 ■ 1695 1100 > 1000 > 100 1697 1500 - > 1000 > 200 1698 1600 700 1703 > 1500 > 50Ü: 200 i.p > 100 > 1000 1600 220 ac, 1705 > 500 I7O6 900 > 400 1707 5OO - > 50 1709 1000 1000 > 500 > 1000 1743 > 500 1744 > 500 1746 500 1747 > 500 500 - 1752 > 500 1000 V1500
J 500 > 125 1755 1000 > 1000 1758 > 500 500 1759 IOO-250 ^ 10OO

009810/1807

5ύϋ i! ife! l-y -_? .. y. (Continuation) 10-20C 50Γ1-100 220 '50 ■ 1 / M y 1000 625 250-501 1762 10-100 '. 1000-150 ( 1763 100-1000 17C4 ) ^ 200 1000 1766 > 1000 100 1767 y 100 > - 1000 3 ^ 0 1770 \ 500 > 1000 > 100 1772 > 500 500 1-100 1774 y 1000 y 20 > 1000 , 50 1775 > 500 ^ 10 > 1000 1777 10J-10C ^ 200 ^ 1000 25-50 1778 y 1000 > 20 100-500 > 200 1779 > 1000 jo> 10-1 oc 1300 100-50C 1781 • 100-1000 100-50C 1782 1000 1734 y 20 1000 1785 > 1000 50-100 1786 ^ 500 1787 y 500 500 1789 } 1000 ) 250 1790 > 500 1000 50-100 1791 > 500 ^ 500 300 1792 ^ 100 950 1793 > 2000 ^ 1000 1794 y 500 ^ 2000 1795 1400 1798 ) 100 ^ 250 1-100 1800 1000 1802 \ 500 y 50G I8O3 > 500 1804 > 1000 I8O5 200 1806 420 ^ 100 I8I5 > 1000 1822 > 1000 1823

009810/1807

1905R83

Aj: omorphine- ■
Dose m ^ / kr Table YI input agitation Vomit
or chew + + Cans
mg / kg 2 i.-. • Π he or-'l reduced + + reduced 25th Pro auk χ,
LA 2 i.p. HTb te Il It reduced reduced more total
protection 25th 16 31 0.1 see above dd S.C. more total
protection more total
protection strong ver
diminishes 10 1532 5 i.p. dog i.p. reduced reduced reduced more total
protection 25th 1674 3 " Would have orally strengthened Il ti reinforced 50 1674 3 " Il i.p. reduced more total
protection 10 1677 3 " It orally Il reduced 50 1687 3 " Il Il ti + 50 1688 0.1 see above Il S. C. more total
protection 25th 1689 3 i.p. dog i.p. reduced + 25th 1C-89 5 " Would have Il ti reduced 25th 1692 2 " It orally It Il 5 1693 3 " It i.p. Il delayed 10 1 ^f: 9 / 0.1 ε.c. 11th S.C. reduced 5 1702 3 OK dog orally more total
protection It 50 1/03 υ, 1 β . ο · Would have see 0. dd 25th I / 03 3 i.p «, riuna i.p. reduced 10 1705 0.1 ε.c. Would have SeC. 25th 1705 3 io? O dog i.p. reinforced 10 17O6 3 " Would have orally reduced 50 1744 2 · ' Il ti more total
protection 50 1746 Z Il Il i.p. reinforced TO 1750 2 » It orally very ver
diminishes 1 1754 2 " ti i.p. reduced 50 1755 2 " ti orally delayed 25th 175? 3 " Il It reduced 50 1758 3 " Il i.p. more total
protection 10 1762 2 " ti .orally reduced 50 1764 ti 1756

009810/1807

Anomorphic
1) 0 se η m ^ / kf: 19ÜRR fabeile VI (jiOrt getting) + ~ no counteraction , in ^ be ■ A-.:;it ^ ti on or chew 83 2 "
2 »
3 "
3 "
; j 11
3 "
3 "
2 "
3 "
2 "
O IJ
2 " i'ier -ryl
It
It
i. '»
Il
Il
Il
Il
ornl
Il Il
Il
reinforced
Il
very much
strengthens
reinfor.-ct
more total
80hut ζ
reinforced
It
• bark ver
dined
more total
protection +
verrr.ir.uert
verse
It
et'v'fis ver
diminishes
amplified
Il
more total
öchut.s
verminaei't
reinforced
reduced
Il product
LA It
It
Il
Il
Il
Il
Il
Il
Il
ti
Il
Il iJÖ33i.
50
30th
so
10
^c o
50
50
50
10 17 * 3
1771
1779
1731
1786
1792
1793
1795
1796
1799
1801
I8O3
1806

009810/1807

BATH ORIGINAL

i, p, -doses ν ■>: * * -33- 190 5683 K ^ uer ·. Thu s- '· + = no counteraction. - Amph3tamines ; ilHbelle, JTII from L /. A -it "tion ;, ü 1u ve P ^ inderb 50 Product; 1 ^C 50 Lik 15th ₇ , _Mis , erb + ? 0 12th + 0 ^L "0 155-3 10 J ■ + > ö 1 ^ 74 12th + 0 10 1689 15th + 1f- »2 15th 0 + 50 160? 15th j + -5 10 ver.:,ö-,;.irt + 50 170c 10 J reduced 20th 1707 15th Terzö place + 50 1 ? Ü? 10 reduced reduced 50 17 *? 10 Il + 10 1745 15th It + 2o 17? 5 15th Il + 20th 1768 10 U min Ie rt 50 1773 10 ■ prevent Il 20th 1775 15th Il + 25th 1787 10 Il reduced 20th 1792 15th 0 Il 60 1800 10 0 It 180 3 O = counteracting; 0 1814 altered 1822 1824

009810/1807

BATH ORIGINAL

product '.Table Λι.ΙΙ Mortal
speed Il L.v-1) or in iir. ; abe 1 Il 16 * 1 mined Il f. ~ orally orally 1552 ip, dose v>:
Ampheterai.'i "> - / k <· Il something ver
diminishes ? 5 Il i. ■ -. 1:74 15th Il reduced 1 i «, -». Il 1'b / 15th Il Il - j Il Il 15th rt.'irk vex -
miüderfc strong verain
changes Il M. 1689 ? .- II It 0.1 Il Il 1692 15th η ii 10m Il: Il 1 ν> 3 15th veiTiir iort 1 orally orally 1β43 2 ^C Il J, 1 i.p. 1tHH 15th Il Il 11th 1-.96 15th ti UJ orally 1 '-> V 27 Il 0.1 i.p. 1Λ * rf-'rk vor-
ni'riei't orally 1703 15th Il Il 1>;> i «p. 1704 25th -: e ; e: iv. ^r ir- 1 orally 1705 15th _lrBllp,. ndprt j 1 Il I7O6 15th ti 1.V 1707 15th Il 10 i.p. 1745 15th II -,1 1745 15th Il 10 1744 15th heavily
ni.idert 10 1750 1- 5fe _L : eir .-: ir- 1 1755 15th 15 vl Reduced 1 1754 15th 25 " 10 1762 15th 1 1762 15th 0.1 17s? 15th 1 1766 15th 1 1767 15th = Ό 1768 20th 10

009810/1807

BATH ORIGINAL

19Q5B83

-If-

Product
IA i, ^ "Doris wjm
/ur.-^het^.^.in "..- ■ · / - j; "derblioh- LA-iJoi; i7j
ir .- / - C- r / Lfi '- "t> 1771 15th ; -: e ^r id 1 'TTiI 1773 15th venni'-ized 1 OK 1?.- '^ It 10 177c 15th reduced 1" 1779 25th ^ e; he "'ir- 0.1 U I- ^f - ', 1 W.
) VZt 1 - V'ί Pfi i lid β r t 10 Λτιη Τ Vi? 15th II 1υ ., r.-l 17 "-. ·» 15th It ' ^J 5 -rfll 17- ^ 2 ¹ ' s "C ??? lc before—
diminishes 10 i.r ·. 1793 15th reduced 1 It 1801 15th It orr <l 1501 15th Il 0.1 i ^r ) 1802 1>^; 11th 1 orally I6O3 Il 10 It I8O3 15th Il 0.1 J-00 1804 15th more total 1 Il 1621 15th ^ gfflftdert 25th orel 1822 15th Il 1 i.p.

009810/1807

1905683 JJiL .υ. ·· -abe fMb-> illegal .la O ■ vo ". 1OB ihand'il- ' Γ
I _i_J "j-? F ^ '^
■■ -. · / <· U UO-I 4th 1 3 1G31 i. ο veplLf-reu.iu-. ''."-' .) ^ 1,-" 1632 If j 15b7 It ν " ¹ I 1» "/'.langriuohf= 3 «.) 1 '"» ° / "» Il ti ^ ro-i ° 3 1689 O P -3.1 6th 169.ί i.;>. V} ro 1693 It ) 4th 1,) 1703 i. ■>. 1 - · - so 1703 orally J ~> 50 1/05 i.% J 1 -j 1707 It J 5 'ti-j 1709 Il 1 r 5) 1709 or ^ l 1 7th 1OJ 1743 i. .j. 1 5 .: J 1750 ti 1 - 2 y 1762 It 1 "--j 1762 orally 1 1) .- j 1771 i.p. ■ O U 1771 orally O 6th '; J 1772 i.p. Q 3 50 1776 η O 5 50 1777 It 2 6th 1773 It O 5 50 1776 ore 1 2 3 100 1783 i.p. O 7th 50 1739 Il O 20th 1790 It O 20th 1791 ti 2 50 1798 ti 20th 1802 η 50 1803 It 50

009810/1807

BATH ORIGINAL

-η-

'! "belle ' ίλ. ι i'Vrtse

product i. r ί ' * LA Il 1804 Il 1822 1835

γο ρUcζ ¹ β π.'ίοΐ 'K ^ i

before. _ V- " · ■ ι- _ "- - J ^c ' O !
ι '*

ÜÖ 3GI1

. £ ίθ -

009810/180 7

BATH

-If-

009810/1807

ί Ι ~ 'Γ ο th · ϋ r:;: i ζ Pt-jric K-.t: .l, ^ i ^ + -1-A ₇ be '/epctK-l'·;-.— + > y 02 ¹ ? X - etv ^ c_ - - " ϊ> ο i.- .. ' 1- / V -ert - - - ir- ,, H - + ■ 50 Il 1 ~ bS / eretäriran - + '; + ⁺ 20th crr> l Ver.tä ^ u, · ⁺ 50
so ΓΑ ¹ . 1 · 3 -Ϊ2 Il κ: ~ o orally i. ;. - II \ ^ταΎΐ · ζ '6 "" 9 rt 50 Jl 1Λ94 M. 50 cr * .l 1: ^ 7 ... ir _ - ti Ί - ^ιΚ ) Il - reduced 5u Il 1702 - Il - Il 50
100 It 1703 G-.' g eiiv.'ir> α: ι _; ■; Il loses; ⁺ 50
50 Il
Lp 1705 It ⁺ - Ι »°. 170? - Il - - 50 17 ^ 6 - - Il - + 2 "> 1750 Ge ge ην ir ku η " + + - 30th pral 1753 - decrease - 50 J-. p. 1755 - gert - 50 1 1757 - Il - + 50 I. 1761 Reinforcement + + O 50 1762 Counteraction 0 0 - 50 Il 1763 - decrease
gert - ■■ - - 12.5
100 ^ r al 1764 - Il - - - 50 L.p. 1768 - It - + 25th 1? 69 Verctä-r ^ np: + + + 50 jral 1771 Counteraction + + + 20th I. 1772 Reinforcement + + ■ 25th I. 1775 Counter effect 20th I. 1778

BAD ORfGINAi.

- ieo3 E: -othc — ie Ptοsis .-, -19 ■ '· elocationunrr) Cans Counteraction Ö8 3 ieo5 Töbeile X (. mg / kg 1805 - ; strong Diarrhea
■ - 50 - -.
-Input « product 1812 changes Ketelonßie ΓΑ 1815 Go '-; e nw ir kunf ^j η - ■ " 50 i.p, ■■ ". 1779 Il in front - - 100 11-23 changes Q orally 1781 - II reduced 50 M. 1735 .Ver'strength.cun · - '· + reduced 20th Ge ^ euvfirkun «: · + _ - ^; ■■■ _.'- $ 0 i.p. . 1789 II + ■ - 25th orally 1791 _ min + . "+" -. '■ - ■ 50 Il 1? 93 et e I't + 11th 1795 - - Il + - .. .. ■ -. - ■. 5O ' i.p » 1800 Ge <re riwi r kunr Il - ίο- ;; - Il ..-_- ■. 100 ti rain effect nd +. - ■. "-" ■ .— -. "■ -.-; 50 ■ Γι _ min - ^: ■ ■ ■ ■ - ■. -50 orally' changes - -i-. _e p »\ - 11th ■ "■ - ■" '■ ■. 50 " ö = Gei-e'iv.'effect · - - = not examined ■■ - ■ - "' . - - "■ .. ■ -. '■ - - + - none -

0 09810/1807

BATH ORiQIMAL,

■ ■ - · 1 diarrhea - HO- cry duration JJo se n Jlin ^ abe G -e £ e η υ i 0 Table JÜ 0 a ProcLuict Tremor Ü 0 75 50 or ^ l LA- 0 0 + 120 10ü i.p. + 0 r -k im; ·: 0 45 50 I. 1636 + Ö .. Salivatio 0 120 50 t 1665 + 0 0 + 30th 50 I. 1688 0. 0 0 0 90 50 I. 1694 + 0 + 0 360 100 orally 1695 0 ■ 0 + 0 H20 50 -.p. 1697 0 0 0 0 50 50 ι 1698 + 0 + 0 90 50 f 1698 0 0 O 0; 75 50 orally 1703 0 0 0 0: -.60 loD. I7O8 0 Θ 0 0 30th 50. OX ¹ el 1709 + 0 0 0 120 'SO Il 1743 0 0 0 ü 120 10 i.p. 1746 0 0 Q ' 0 ' 30th 10 orally 1754 Ü Ό 0 Ü 120 50 Il 1758 0 0 0 0 30th 50 ¹ 1758 0 0 O ü 30th 50 L.p. 1762 0 0 0 ü 75 50 I. 1763 0 0 0 0 120 10 ) ral 1763 0 0 0 0 120 1 ..p. 1772 0 0 O 0 120 50 ι 1778 Ö 0 O 0 ⁶⁰ 25th ) ral 1778 0 0 O + 30th 50 ι 1782 + 0 0 0 120 50 I. Ί788 " + 0 0 0 60 50 I. 1791 + Ό 0 0 120 50 I. 1794 0 - 0 O 0 60 10 ..p. 1795 0 0 + + 60 50 > ral 1798 0 0 = counteraction; 0 120 50 Il 1798 + 0 Counteraction 1803 O 1804 0 + + = none

009810/180?

Tnbelle. XxI
- ■ "■ _- 1905683 50 j ..- -. ■ ...; - ■■ ... -ν-
J Change of Jleaktiorisseit true to Scinne ^r a 50. product 5 '' ■ -
■ ·; · -..-_ + 70-:
ι ...., - ■ " oral doses 1 + .76 -; -. .-; - mg / kg 10 1655 +35. -. -;, .50: 1557 + 35. _50: 1676 + 42. ■ 1676 + 69 -. ■ ''. 25th 1676 + 52 '25 · ■■ 1677 + 33 50 ..'- ■ ' 1587 + 35.; ■ - ■ '-' -5- - \: 1688. + 26 50 .. 1689 + 77 JO. 1692 + 30 .. \ ■ '-, * ■' - 10 - ■■ '. ■.' .: 1693 + 57 '. ' 50 1693 + 33 ,., - 50 ' 1694 + 78 '■ - ^: --- V " 50 1703 + 41 x; 50 -.- ■ '■■ 1704 + 70. ■ - '.. 50 1706 '+ ■ 5β- ".' ■■ '; ■ · ...: ... \ 50. ■■ /. i 1707 - + 28 \ λ. - ; "■; 50
- ti - I77O + .50: 50 ',.; ■ -: 1773- + 30 . . ■■■ - ';. "■■■. 50 ' 1779 + 52.: .-. ; 50 - ■., -. - 1781 + 30:; : 50 I782 + 17 ■■■; - ■. 50 1786 .- + -33. - ".... _: -. ■ '.-- ■."-.'"■'" ■ " 50 '. I79O - 9; -. . . ': -'-; ■ .- ' 50: 1791 . + 30.. ; - ■ ■: ■■ - ^: ... _Λ , 30 : 1795 - 33 V · ■ '- 50 1795 + 25 .... . :; . ■ '.- .. - "" ·. ;. ". 75 1798 -15-. - ■; - '. ; - '.; ■ ,. . 1813 + 60 1814 +100 - _.-,. '..' I8I5

009810/1807

BATH ORIGINAL

-4t- Papaverine Table XV 1/1 product Effect compared to s / 1- LA Atropine 1/5 1665 1 / 5Oo 1/5 1639 1/730 2/1 1690 - ■ " 1/1 1691 - 1/5 1692 - 1/2 1093 1/300 1/1 1694 - 1/3 1693 - 1699 1/1000 - 1702 - ■. - -. . 1707 1/300 1764- 1/300 1779 1/750 1/5 1782 1/500 1/1 1789 1/500 1793 1/1000 1793 1 / 1OpO 1799 1/300

009810/180 7

Table XIII_ cramps mortality 1SÖSB83 ■■: ''Product total protection reduced χ «.p« cans M. ti Il totalei " ¹ protection mg / kg _ "-" · 1674 Il Il Il Il 20 -; ■; - ■■■ "'■." ..' 1689 Reinforcement elevated 10 ';' / 'V 169? total protection total protection 50 / 1695 IJ Il reduced 20 - - 1703 protection total protection - ■ 20 "& rass I7O6 ti reduced . '. 20; ν 1707 ti Il 20 ■ '■.' .; "V 1709 Reinforcement elevated 20th 174-6 total protection. total protection 20 _; ■ V 1750 Reinforcement elevated '20 1752 protection reduced '1766 Reinforcement elevated 20th 1767 protection diminished. 20 : -. ': -; 1768 Reinforcement elevated 20 V: ■, :: 1778 Il Il 7 20 : '_' ■ ': ^; ■: 1781 protection reduced 2q: '■ . -7 1784 Reinforcement without Λ / effect 20 '-. '■'. '■■; ; - ■ ' 1803 total protection total protection 20th 1614 Reinforcement
- ■ - ■ -
".:" ■ "" ■ elevated 23 "7 ■; -'- / ■ ' 1822 80 ■ 7 .- ': ■:' 1823 20th

009810/1807

Table XEV jSinuch sleep time Sleep duration i.p "-D03GIl product LX extended shortened 20th 1674 Il - '■ (.. 20th 1639 extended extended 20th 1693 shortened - ■ - ■ 20th 1697 extended extended 20th iyo4 shortened very extended ■ 20 1707 Il extended 20th 1749 ti Il 20th 1750 extended - 20th 1755 shortened extended 20th 1756 Il Il 20th 1757 ti Il 20th 1759 Il - 20th 1762 It extended 20th 1763 ti K 20th 1764 Il 20th 1779 extended - 20th 1782 shortened extended 20 " 1784 extended - 20th 1791 shortened - 20th 1800 - extended 20th 1803 somewhat shortened Il 20th 1806 shortened It 20th 1808 Il - 20th 1815 extended - 20th 1822 20th 1823

009810/1807

Claims (1)

Claims = 1. Therapeutically effective substituted ^ -amino - ^ - hydroxy methyl-6-amin.otriazine-1,3,5 of the general formula R-CH-G where mean: ' R - hydrogen, an alkyl, methylenedioxyphenyl or a phenyl group optionally mono-, di- or trisubstituted _{by halogen, alkyl- S haloalkyl or alkoxy radicals} R ¹ and R ¹ '- either hydrogen, an alkyl, alkenyl, cycloalkyl, dialkylaminoalkyl, piperidinoalkyl or morpholinoalkyl group, only one of the substituents R ¹ and R ¹ ' being hydrogen or alkyl, or NR ¹ R '' ■ "an® optionally C-alkyl-substituted heterocyclic group with a second hetero nitrogen atom, which by-ch an alkyl, alkenyl, hydroxyalkyl or ei-? N an optionally substituted phenyl radical substituted ^J Salts of the traizins (Ι) _Φ 1 2. Triazines (I) according to claim 1, containing as alkyl » 009810/180 7 - ag- - 5 * [triazines (I) according to claim 1 and 2, containing as heterocyclic group NR ¹ R ' ^f a group consisting of 5 $ 6 or 7 ring atoms · 4, triazines (I) according to claim 1 to 3, in optically active or racemic form. 5, triazines (I) according to claim 1 to 4, with a £ -Hydroxyn «-propyl-, -n-heptyl-, -η-benzyl-, -p-chlorobenzyl-, -pf luorbenzyl-, -p-methylbenzyl- or -3 _e 4 '- (methylenedioxy) benzyl group in the 4 position and an allyl, (diethylaminoethyl) -, (N-methyl-N-dimethylaminoethyD-, (N-methyl-N-diethyl-aininoethyD-amino- Group or a (4'-methyl) -, (4'n-propyl) - or (4 ^l -allyl) -piperazinyl group in the 6-position · 6, a process for the preparation of the triazines (I) according to claim 1 to 5, characterized in that a C £ · hydroxycarboxylic acid of the formula R-OH (OH) - CO - OH II with a biguanide of the formula H ₂ N - O (NH) - NH - G (NH) - NR ¹ R ¹ 'III in which R, R ¹ and R ¹¹ or NR ¹ R' ^{1 have} the above meaning, and from the reaction mixture in the usual way the triazine (I) secretes 7 "The method according to claim 6, characterized in that the acid (II) is in the form of an anhydride, aoyl halide, 009810/180 7 90 568 3 Uses esters, amides or hydrazides 8β Method according to claim 6 and 7 »characterized in that that you can carry out the reaction at at least 1OO ° C in the absence of solvent and catalyst carried out 9o method according to claims 6 and 7 »characterized» that the reaction is carried out in the presence of an alkaline catalyst *, such as alkali metal alcoholate, preferably sodium methylate, carries out « 10. The method according to claim 6, 7 and 9, characterized in that that one starts with the hydrohalide of the biguanide (III) the latter with as much of the alkaline catalyst in Freedom presupposes that there is an equivalent left, and with Hil < fe of the latter then the biguanide (III) with the stoehiometric Amount of ci ^ -hydroxycarboxylic acid (II) reacted 11. The method according to claim 6 to 10, characterized in that the separation of the triazines obtained (I) from the Reaction mixture by adding water and optionally subsequent Extraction with a solvent such as methylene chloride as well as recrystallization of the obtained Bh product aut a solvent such as water, acetonitrile, alcohols or ketones 12 Therapeutically effective substitutes * 009810/1807 .- 24 - NH ₂ -G-NH-C- O - NH - C - IT NH NH ^ R * '·' in which R ¹¹¹ "and R ¹¹ " denote either hydrogen, an alkyl, bialkylaminoalkyl, piperidinoalkyl or morpholinoalkyl group, only one of the substituents H ¹ and R "being hydrogen or alkyl, or NR '· ¹ R '·''- an optionally C-substituted heterocyclic group with a second heterocyclic atom which is substituted by an alkyl, alkenyl, hydroxyalkyl or an optionally substituted phenyl radical, the alkyl radical not being a methyl radical if the heterocyclic group is a Is piperazino group. 13 · Biguanide (IV) according to claim 12, containing as alkyl, Alkenyl and hydroxyalkyl radicals lower radicals 14, biguanides (IV) according to claim 12 and 13 »containing as heterocyclic group NR ¹¹¹ R ¹¹¹ 'a group consisting of 5» 6 or 7 ring atoms ». 15 · Process for the preparation of the biguanides (IV) according to claims 12 to 14, characterized in that a salt of an amine of the formula HNR ¹ "E""or a corresponding heterocycle in which R ^1! · And R ¹¹ ' ¹ respectively, NR ¹ ' ¹ R' · '' have the above meaning, with a cyanguanidine of the gormel E ₉ S - G (NH) - NH- QN , in melt flow or in 009810/1807 - as. - a solvent such as butanol or ethylene glycol ether implemented 16. Use of the triazines (I) according to claim 1 to 5, in Combination with a therapeutically acceptable carrier as therapeutic remedies acting on the central nervous system 17 · Use of the triazines (I) according to claim 16 in oral parenteral or rectal daily doses of about 2 to 1000 mg, or in individual doses of 1 to 500 mg _e 0 09810/1807